Heterocyclic pyrazines

ABSTRACT

PROCESS FOR ALTERING THE FLAVORS OF PRODUCTS, INCLUDING FOODSTUFFS AND TOBACCOS, WHICH COMPRISE ADDING THERETO A SMALL BUT EFFECTIVE AMOUNT OF AT LEAST ONE HETEROCYCLIC PYRAZINE HAVING THE FORMULA:   2-R1,3-R2,5,6-(-CH2-Y-CH2-)(-R3)(-R4)(-R5)(-R6)PYRAZINE   WHEREIN Y IS -O-,-S-,-CH2-O-,ORCH2-S-, AND R1,R2,R3,R4,R5,AND R6 ARE THE SAME OR DIFFERENT AND REPRESENT HYDROGEN AND LOWER ALKYL; THE PRODUCTS SO PRODUCED; FLAVORING AND FLAVOR-ENHANCING COMPOSITIONS CONTAINING SUCH HETEROCYCLIC PYRAZINES; AND NOVEL HETEROCYCLIC PYRAZINES AND PROCESSESSES FOR THEIR PRODUCTION.

United States Patent 3,647,792 HETEROCYCLIC PYRAZINES William J. Evers,Long Branch, Ira Katz, Elberon, Richard A. Wilson, Edison, and Ernst T.Theimer, Rumson, N.J., assignors. to International Flavors & FragrancesIn c., New York, N.Y.

No Drawing. Filed May 4, 1970, Ser. No. 34,583 v Int. Cl. C07d 51/76 US.Cl. 260-250 R 8 Claims ABSTRACT OF THE DISCLOSURE Processes for alteringtheflavors of products, including foodstuffs and tobaccos, whichcomprise adding thereto a small but effective amount. of at least oneheterocyclic pyrazine having the'for'mula:

' BACKGROUND OF THE INVENTION The present invention relates toheterocyclic pyrazines and their use in processes and'compositions foraltering the flavors of various materials such as tobaccos, foodstuffs,and the like, as well as the novel pyrazines and processes for producingthem. i

' Because of the .tremendous consumption of foods, tobaccos, and othermaterials, there has been an increasing interest in substances'andmethods for imparting flavors to such consumable materials. Thisinterest has been stimulated not only because of the inadequate quantityof natural flavoringmaterials available, but perhaps even moreimportantly, because of the need for materials which can combine severalnuances, will be more stable than natural materials, will blend betterwith other flavors or flavoring composition components, and willgenerally provide superior products.

'There' have recently. been suggestions that certain pyrazinederivatives have flavors which'might be useful in fqodsand otherconsumable materials. For example, tetramethylpyrazine has beensuggested for use with vanillin in chocolate flavors, acetylpyrazine hasbeen used in tobacco and foods, and methoxypyrazine has been said toimparta nut-like flavor to foods.

THE INVENTION materials by adding thereto a small but elfective'amountof at least one heterocyclic pyrazine having the formula 3,647,792Patented Mar. 7, 1972 wherein Y represents -O, 'S, --CH -S, or CH O, andR R R R R and R represent hydrogen, alkyl, or alkylene and are the sameor different. The invention also contemplates flavoring andflavorenhancing compositions containing such pyrazines, as Well a; thenovel pyrazines and the processes for preparing t em.

=More specifically, the heterocyclic pyrazines according to thisinvention are pyrazines to the b side of which are fused fiveandsix-membered oxygenor sulfur-containing rings such as dihydrofuran,dihydrothiophene, dihydropyran, and the sulfur analog of such pyran.Such rings can be substituted with one or more alkyl or alkylene groups.The pyrazine ring can also be substituted with one or tWo alkyl oralkylene groups, and such substituents on the heterocyclic ring can, insome cases, be geminal. In some instances one or the other of the ringscan be substituted with an alk-adienyl group. It is generally preferredin practicing the present invention that the substitutentbe hydrogen ora lower alkyl group, particularly alkyl groups having from one to sixcarbon atoms, and most preferably alkyl groups having from one to threecarbon atoms.

Thus, the present invention contemplates 5,7-dihydrothieno[3,4-b1pyrazines having the formula:

7,8-dihydro 5H thiapyrano[3,4-b]pyrazines having the formula:

and 7,8-dihydro-5H-pyrano[3,4-b1pyrazines having the formula:

Exemplary of heterocyclic pyrazines prepared according'to this inventionis 2methyl-5,7-dihydrothieno[3,4-b]

pyrazine having the formula:

This material is a white crystalline solid having a roasted r,nut-lilteodor; Another pyrazine according to this invenand a roastedaroma character. A further illustrative pyrazine according to thisinvention is 5,7-dihydrothieno- [3,4-b]pyrazine having the formula:

and being a solid melting at 8889 C. with a roasted nut flavor.

The novel pyrazines prepared according to the present invention can beobtained by a number of reaction routes. The dihydrothienopyrazines canbe prepared by reacting a 3,4-diaminothiophane or a monoor dialkyl or-alkylene 3,4-diaminothiophane with an a-diketone under ringclosingconditions. The diaminothiophane and the diketone are admixed and astrong alkali metal hydroxide is added. The hydroxides of sodium orpotassium are desirably used.

The alkaline mixture is then treated with oxygen at a temperature offrom to 50 C. to provide a satisfactory reaction rate while minimizingundesirable side reactions and the ebullition of the reactants. Theoxygen can be pure or can contain inert diluents. It has been founddesirable to use air as a source of oxygen.

The oxygen is added to the reactants by sparging or otherwise bubblingthe gas through the reaction mixture. At the temperature used herein,the times for the reaction range from one to 24 hours, and it isdesirable to carry out the reaction such that it attains a high degreeof completion in from about 8 to 12 hours.

The reaction is desirably carried out in an inert reaction vehicle topermit better control over the reaction temperature and to improvemixing of the reactants. The preferred inert reaction vehicles aresolvents and include alkanols, preferably lower alkanols such asmethanol, ethanol and the like, oxygenated solvents such as ethyl ether,ethylene glycol, and the like.

After the reaction is completed, the pH of the reaction mixture isreduced by the addition of an acid, desirably a strong mineral acid suchas dilute sulfuric acid, preferably 10% to 50% sulfuric acid. The pH-need not be reduced to neutrality, but it is desirable that it bereduced to or below 9, and it is generally preferred to reduce the pH to8.0-8.5, but not lower than about 7.

The dihydrofuropyrazines are conveniently prepared by reacting a vicinalalkadione dihalide with 1,2-diaminoethane or a mono or dialkylderivative thereof. Thus, a dione having the formula:

wherein each X is a halogen atom and R and R are hydrogen or lower alkylcan be used. In carrying out I -40 C., are utilized. At temperaturesabove 0 C. the reaction proceeds too vigorously, is difficult tocontrol, and provides unwanted by-products, while at temperatures "below40 C. the reaction rate becomes very sluggish. It is accordinglydesirable to utilize temperatures of from 0 to 40 C. Temperatures offrom about 5 C. to about 20 C. are preferred.

After this first step of the reaction is completed, the mixture isoxidized under alkaline conditions to produce the dihydrofuran ring.The'oxidation. is carried out at an alkaline pH, desirably in thepresence of an alcoholic alkali metal hydroxide. Preferred alcohols arethe lower alkanols, particularly methanol and ethanol. Preferredhydroxides are sodium and potassium.

The temperature of the oxidizing reaction can range from 20 C. to 50 C.At higher temperatures the rings can be oxidized, and at lowertemperatures the reaction proceeds with a very low velocity.

'Ilhe thiapyranopyrazines are prepared by reacting l,2-' diaminoethaneor l-alkyl or 1,2dialkyl derivatives thereof with 3-chlorothiapyra'n 4one or alkyl-substituted derivatives thereof, desirably at the lowtemperatures described herein. The pyrans are similarly prepared fromthe reaction of such diamines with 3-chloropyrones or alkyl-substitutedderivatives thereof. The pyrazine is produced from the reaction productsby oxidation in the presence of alkalis as described above.

It will be understood by those skilled in the artthat the intermediateand the final productsprepared herein can be neutralized, washed, anddried to obtain the desired substances. The novel cyclic pyrazines canbe obsained in purer form or in substantially pure form by conventionalpurification techniques. Thus, the products can be purified and/orisolated by distillation, extraction, crystallization, preparativechromatographic techniques, and the like. It has been found desirable topurify the heterocyclic pyrazines by fractional distillation undervacuum.

It will be appreciated from the present disclosure that the heterocyclicpyrazines and mixtures thereof according to the present invention can beused to alter, vary, fortify, modify, enhance, or otherwise improve theflavor of a wide variety of materials which are ingested, con sumed, orotherwise organoleptically sensed. Such'pyrazines are accordingly usefulin flavoring compositions and in flavor-enhancing compositions.Aflavor-enhancing composition is taken to mean one which contributes apart of the overall flavor impression by supplementing or fortifying anatural or artificial flavor in a material.

When the pyrazines of this invention'are used in a flavoring or aflavor-enhancing composition, they can be combined with conventionalflavoring materials including organic acids such as fatty, saturated,unsaturated, and amino acids; alcohols, including primary and secondaryalcohols; esters; carbonyl compounds including ketones and aldehydes;lactones; other cyclicorganic materials including benzene derivatives,alicyclics, heterocyclics such as f-urans, pyridines, other pyrazinesand the like; sulfur-containing materials including thiols, sulfides,disulfides and the like; proteins; lipids, carbohydrates, so calledflavor potentiators such as monosodium glutamate, guanylates, andinosinates; natural flavoring materials such as cocoa, vanilla, andcaramel; artificial flavoring materials such as vanillin; and the-like.

It will be appreciated that the types and amounts of materials selectedfrom the foregoing groups of materials will depend upon the preciseorganoleptic character desired in the finished product and, especiallyin the case of flavoring compositions used to enhance other flavors,will vary according to the foodstuff to which flavor and aroma are to beimparted.ilnorganic materials such as sodium chloride and freshnesspreservers such as butylated hydroxyanisole and propyl gallate can beadded for their adjuvant or preservative effects on the flavoringcomposition.

The pyra-zines, or thecornpositions incorporating them as mentionedabove, can be combined with one or more vehicles-or carriers for addingthem to the particular product. Vehicles can be edible or otherwisesuitable materials such as ethyl alcohol, propylene glycol, water, andthe like. Carriers include'materials such as gum arabic, carrageenen,other gums, and the like. The pyrazines can be incorporated with thecarriers by conventional means such as spray-drying, drum-drying, andthe like. Such carriers can also include materials for coacervating thepyrazines (and other flavoring ingredients, as present) to provideencapsulated products. When the carrier is an emulsion, the flavoringcomposition can also contain emulsifiers such as monoand diglycerides offatty acids and the like.- With these carrier or vehicles the desiredphysical form of the composition can be prepared.

The pyrazines according to the present invention can be utilized in aWide variety of foodstuffs, tobaccos and other consumable products. Asused herein, the term foodstulfs is taken to mean foods and beveragesfor human consumption and veterinary and other products, such as dogfood, cat food, and the like. Thus, it will be appreciated that thepyrazines of the present invention can be used in snack foods, breakfastfoods, baked goods, nut butters suchas-peanut butter and other spreadsincluding cheese spreads, milk, butter and other dairy products, meatand poultry products, fried foods,-and a wide variety of othermaterials.

Itxwill be understood by those skilled in the art that the pyrazinesaccording to this invention can be added to the zmatrials to be flavoredat any convenient point in production of the finished product. Thus,when the pyrazines are used to alter or otherwise vary the flavor of afoodstuff, they can be added in the original mixture, dough,.:jemulsion,batter, or the like prior to any cooking or heating operation.Alternatively, they can be added at at later stage of processing ifvolatilization losses would be excessive during the earlier processing.

When the materials are used to treat tobacco products, for example, theadditives can be applied in a suitable manner by spraying, dipping, orotherwise. Tobacco products will herein be understood to include thoseused for the production of pipe, cigar, and cigarette tobaccos, snuff,and chewing tobacco. The pyrazines can be applied to the casing or finalspray treatment of the tobacco, or they can be applied at some earlierstage of curing.

The quantity of pyrazines or mixtures thereof utilized should besufiicient to impart the desired flavor characteristic tothe product,but on the other hand, the use of an excessive amount of the pyrazinesis not only wasteful and'uneconomical but in some instances too large aquantity may unbalance the flavor or other organoleptic propertytof theproduct to be consumed. The quantity used will varydepending upon theultimate foodstuff, tobacco product,-or other consumable product; thequantity of flavor present initially in the product; the further processor treatment steps to which the product will be subjected; regional andother preference factors; the type of storage, if any, to which theproduct will be subjected; and the pre-consumption treatment, such asbaking, frying, casing, and so on, given to the product by the ultimateconsumer.

The ultimate compositions can accordingly contain from about 0.01 partper million (p.p.m.) to about 100 p.p.m. More particularly, in foodcompositions it is desirable to use from about 0.05 to about 50 p.p.m.and in certain preferred embodiments of the, invention, from about 0.1to about 20 p.p.m. of the pyrazines are included in the finishedproduct. On the other hand,'tobacco compositions can contain as littleas 0.1 p.p.m. and as much as 100 p.p.m., depending upon whether acigarette tobacco, a pipe tobacco, a cigar tobacco, a chewing tobacco,or snuff is being prepared.

All parts, proportions, percentages and ratios herein are by weightunless otherwise indicated.

The amount of pyrazine or pyrazines to be utilized in flavoring orflavor-enhancing compositions can be varied over a wide range dependingupon the particular quality to be added to the foodstuffs, tobacco, orother consumable material. Thus, amounts of one or more pyrazinesaccording to the present invention from about 0.1 up to or can beincorporated in such compositions. It is generally found to be desirableto include from about 0.5 to about 25% of the heterocyclic pyrazines insuch compositions.

The following examples are given to illustrate embodiments of theinvention as it is presently preferred to practice it. It will beunderstood that these examples are illustrative, and the invention isnot to be considered as restricted thereto except as indicated in theappended claims.

Example I.Preparation of methyl dihydrothienopyrazine A 500 ml. flask ischarged with 0.88 g. of 3,4-diarninothiophane in 100 ml. of ethanol andcooled to -20 C., and a solution of 0.54 g. of pyruvic aldehyde in 50ml. of 95% ethanol is added during 15 minutes. After warming to roomtemperature 0.27 g. of sodium hydroxide in 20 ml. of 95% ethanol isadded, and the mixture so formed is heated at reflux for two hours.After cooling, solvent removal in vacuo gives a brown tar. Triturationwith methylene chloride, followed by solvent removal in vacuo, gives0.70 g. of residue. Column chromatography followed by preparative gaschromatography gives a white crystalline sample of2-methyl-5,7-dihydrothieno[3,4-b] pyrazine.

Mass spectroscopy of the white crystalline solid so produced shows peaksof m/e ratios of 152, 151, 39, 41, and 57. UV (ultraviolet) spectroscopyshows x at 213 and 276 Km with a shoulder at 307 m PMR (proton magneticresonance) in deuterochloroform shows a singlet at 8.24 accounting forone proton, a singlet at 4.23 accounting for four protons, and a singletat 2.55 accounting for three protons. This substances has a roasted nutaroma. It can be used in flavoring food and tobacco products, both toprovide popcorn or roast cereal flavor notes and to enhance and interactwith other fragrances and flavor notes.

Example II.-Preparation of dihydrodimethylfuropyrazine A three-neckreaction flask fitted with a gas-inlet, thermometer, magnetic stirrer,and drying tube is charged with 2.0 g. (0.0073 mole) of2,5-dibromo-3,4-hexanedione in 20 ml. of methanol. The mixture is cooledto 10 C. with stirring, and 0.44 g. (0.0073 mole) of 1,2-diaminoethaneis added. The temperature rises to -5 C. during the addition, and thereaction mixture is then stirred at 10" to 20" C. for two hours.

A pellet of potassium hydroxide is added and air is bubbled through themixture. The mixture is permitted to reach room temperature while theair is being added, and an additional small quantity of a solution ofsodium hydroxide in methanol is added. The air bubbling is continued foran additional eight hours.

The oxygenated mixture so obtained is poured into 10 ml. of water and pHis adjusted to 8 with 20% aqueous hydrochloric acid. This mixture isthen extracted, five times with '50 ml. portions of methylene chloride.The extracts are dried over sodium sulfate, filtered, and concentratedto obtain 0.5 g. of a dark brown oil.

The oil is resolved by gas-liquid chromatography (GlLC) to obtain5,7-dihydro 5,7 dimethylfuro[3,4-b]- pyrazine. Thismaterial has a sweetroasted aromain a one percent ethanol solution. PMR analysis confirmsits structure.

Ina one p.p.m. aqueous solution, this material is near the thresholdlevel of its taste; in a 3 p.p.m. aqueous solution it has a popcornflavor note; and at 10 p.p.m. it shows a roasted nut character,reminiscent of hazelnut and peanut. At 10 p.p.m. in a 10 percent aqueoussucrose solution, it provides a dominating roasted nut character.

At 3 p.p.m. in 4 percent aqueous salt solution it has a yeasty roastedtaste, while at p.p.m. it has a salted roast nut taste.

A chicken broth is prepared, and 3 ppm, of the material of Example II isadded. The aroma and taste of roast chicken are imparted to the broth,and the general taste of the broth is improved. A beef broth isprepared, and 10 p.p.m. of the material of Example II is added. Thematerial imparts a baked potato character to the broth. Thisfuropyrazine is judged to be suitable for imparting roasted flavor notesto peanuts, and is also suitable for malt flavors.

Example III.-Preparation of dihydrothienopyrazine To a refluxingsolution of 5.6 g. of sodium hydrosulfide in 300 ml. of methanol isadded a solution of 8.8 g. 2,3- di(chloromethyl)pyrazine in ml. methanolduring ten minutes. After refluxing for an additional 1.5 hours, thereaction mixture is allowed to stand at room temperature (about 23 C.)for 70 hours, and then refluxing is repeated for an additional threehours.

.The mixture is cooled to room temperature and the methanol is removedto provide a dark brown solid. This solid is extracted with 300 ml.methylene chloride, and the methylene chloride is removed in vacuo toprovide 5.3 g. of a brown oil.

The oil is chromatographed several times on silicic acid withmethanol/methylene chloride mixture to provide a product which uponcrystallization from a 95 ethanol solution yields 0.18 g. of 5,7dihydrothieno[3,4 b] pyrazine. 1

This thienopyrazine derivative is a solid melting at 8689 C. Sublimationin vacuo provides 0.10 g. of material melting at 888'9 C. Massspectroscopy shows peaks at m/e ratios of 138, 137, 57, 41, 29, and 39.UV analysis shows a A at 211 and 255 mu with a shoulder at about 309 mPMR in deuterochloroform shows a singlet at 8.36 accounting for twoprotons and a singlet at 4.2 6 accounting for four protons.

The odor of a 0.01 percent solution of this material in 95% ethanol isnear the threshold level and is light roasted nut with a popcornlikenote; at 0.1 percent in such ethanol, the odor is roasted nut,especially redolent of peanut and hazelnut. The taste of this materialin water at the 0.02 p.p.m. level is characteristic of roasted peanut,bread crust, with an odor reminiscent of fresh milk; at 0.2 p.p.m., abaked goods, bread crust, roasted nut taste; at 2 p.p.m., a sweetcharacteristic nut flavor with no bitter aftertaste.

In sucrose solution at 4 p.p.m. the dihydrothienopyrazine has a flavorlike baked goods, while at 3 p.p.m. in salt water there is a fried cornchip, salted peanut flavor character. This pyrazine derivative issuitable for roasted nut flavors, baked goods flavors, and otherflavors.

Example IV A cheddar cheese flavoring formulation is prepared byadmixing the following ingredients in the amounts indicated:

Ingredient: Amount (parts) Methyl hexyl ketone 11.5 Diacetyl 14.2isoValeric acid 40.8 Hexanoic acid 158.9 Butyric acid 244. 8

Caprylic acid 534.8

Dihydrothienopyrazine produced in Example The foregoing cheese formulais incorporated into a bland cream cheese spread and evaluated oncrackers. A good sharp cheddar flavor is imparted to the cheese spread.

What is claimed is:

1. A heterocyclic pyrazine having the formula" R3 R1 R jd 4 I R q s 7and R R R R R and R are the same or difierent and represent hydrogen orlower 'alkyl having one; to three carbon atoms. I

2. A heterocyclic pyrazine according to claim 1 wherein Y is S-.

3. A heterocyclic pyrazine according to claim 1 wherein Y is --S and Ris methyl; 1

4. A heterocyclic pyrazine according to claim 1 wherein Y is O and R andR are methyl.

5. A process for preparing dihydrothieno pyrazines which comprisesreacting 3,4-diaminothiophane or monoor dialkyl-3,4-diaminothiophanewith pyruvic aldehyde in the presence of an alkali-metal hydroxide: andsubsequently dehydrogenating the reaction product;

6. A process for preparing dihydrofuropyrazines which comprises reactingat a temperature of 0 to 40" C. a dicarbonylic material having theformula wherein each X is a halogen atom and R and are hydrogen or loweralkyl, with 1,2-diaminoethane, 1-al'kyl-- 1,2-diaminoethane, or*l,2-dialky1=1,2-diaminoethane.to

obtain an intermediae reactionproduct and subsequently.-

References Cited FOREIGN PATENTS i 1,135,471 8/1962 Germany 6.

NICHOLAS s. RIZZO, Primary Examiner having from one to:

